tbuckley/cabot-search huggingface dataset:
Final analysis results from a multicenter clinical study of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy in patients with cT2-T4aN0M0 MIBC.
Authors: Tianxin Lin, Kaiwen Li, Jinhai Fan, Shaogang Wang, Dexin Yu, Tao Xu, Jiaju Lyu, Tao Qin, Zheng Liu, Kaijie Wu, Jinyou Wang, Qi Wang, Jie Min, Zhiquan Hu, Fan Li, Zhiqiang Zhang, Luping Yu, Sentai Ding, Jian Huang
Journal: Journal of Clinical Oncology (2023)

4585 Background: To evaluate the efficacy and safety of tislelizumab combined with gemcitabine and cisplatin as neoadjuvant therapy for patients (pts) with clinical T2-T4aN0M0 (cT2-T4aN0M0) muscle-invasive bladder urothelial cancer (MIBC). At predefined interim analysis, the study has met the first stage aim. Here reported the results of the predefined final analysis. Methods: This phase II study enrolled pts tolerated with the cisplatin therapy. Eligible pts received tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m 2 D2, and gemcitabine 1000 mg/m 2 D1 and D8 every 21 days for four cycles. Radical cystectomy (RC) was performed within 6 weeks after last dose treatment. The primary end point was pathologic complete response (pCR, pT0N0M0). Secondary end points were pathologic downstaging (≤pT1N0M0) (pDS), EFS, OS and safety. Simon two-stage design was used. If &gt;5 pts achieved pCR in the first stage (n=22), study would proceed to the second stage and enroll 33 additional pts. If &gt;18 of 55 pts achieved pCR, we would deem the study to have met the primary endpoint. Results: At the data cut off time of 14 th Dec 2022, 63 pts (38 cT2, 19 cT3, and 6 cT4a) have completed neoadjuvant therapy, with median age of 64 (48-75) years. The median relative dose intensity of tislelizumab, cisplatin and gemcitabine were 92.3%, 85.7% and 85.6%, respectively. At this time, 55 pts underwent RC and completed 30 days post-surgery follow-up. The median time from last dose to RC was 4.4 (range: 0.6-13.3) weeks. Eight pts refused RC. Among 55 efficacy evaluable pts, 27 (49.1% [90% CI, 37.4-60.9]) pts achieved pCR, while 41 (74.5% [95% CI, 61.0-85.3]) pDS. Pts with cT2 achieved 55.6% (20/36) pCR and 86.1% (31/36) pDS. Among 14 non-responders, 3 of them (1 cT2, 2 cT3) achieved pT0, but with pathologic N1. Clavien-Dindo grade ≥3 postoperative complications occurred in 7.9% pts. Most common neoadjuvant therapy related AEs of any grade were hematologic toxicities (88.9%), nausea (77.8%), and vomiting (50.8%). Grade ≥3 neoadjuvant therapy related AEs occurred in 60.3% pts, which were hematologic toxicities (58.7%) in most. The frequently occurring immune-related AEs (irAEs) (&gt;5%) included dizziness (14.3%), fatigue (12.7%), ASL/ALT increased (7.9%), rash (7.9%), pruritus (7.9%), and GGT increased (6.3%). Grade ≥3 irAEs occurred in 2 pts (pneumonia, n=1; cardiomyopathy, n=1). Conclusions: The study met its primary endpoint. Neoadjuvant tislelizumab combined with gemcitabine and cisplatin showed promising anti-tumor activity with high pCR and well tolerance in MIBC pts. Clinical trial information: ChiCTR2000037670 .
MOSAIC: Multi-Omic Spatial Atlas in Cancer, effect on precision oncology.
Authors: Joseph Lehar, Elo Madissoon, Jerome Chevallier, Jean Baptiste Schiratti, Atanas Kamburov, Rodrigo Barnes, Carla Haignere, Anna Joy, Agnès Dodacki, Caroline Hoffmann, Silvia Lopez Lastra, Almudena Espin Perez, Quentin Bayard, Katharina von Loga, Hubert Chaperon, Jean-Philippe Vert, Eric Durand, Vassili Soumelis, Gilles Wainrib, Thomas Clozel
Journal: Journal of Clinical Oncology (2023)

e15076 Background: Precision oncology aims to first break diagnoses into biologically distinct subtypes, then pursue personalized therapies for each group of patients ( Garraway et al, J Clin Onc, 2013). This strategy is enabled by recent advances in technologies for medical imaging, molecular profiling, and artificial intelligence. Spatially resolved molecular profiling (“spatial omics”) is an emerging technology that harnesses all three of these advances ( Navarro et al, Science, 2016; Rao et al, Nature, 2021). Cancer is driven by localized interactions between tumor cells, immune and non-immune stromal components. Methods: Spatial omics studies have revealed specific cell types and pathways that control those tumor-microenvironment crosstalks ( Hunter et al, Nat Comm, 2021; Alon et al, Science, 2021), involving both innate and adaptive immunity ( Binnewies et al, Nat Med, 2018). Identifying new cancer subtypes based on the spatially localized tumor-host interactions across many patients have the potential to revolutionize immuno-oncology. The advances in utilizing AI-based methods have so far been unattainable due to a small number of patients in spatial omics studies. Results: Here we present the MOSAIC project - a collaborative initiative across industry and top oncology hospitals to build the largest collection of spatial omics data in cancer. We combine comprehensive clinical annotation with new deep profiling methods to both discover cancer subtypes and identify drug targets and biomarkers within them. MOSAIC aims to generate multimodal data for a total of 7,000 patients in seven cancer indications. Data modalities will include spatial and single cell transcriptomics and proteomics, bulk molecular profiling, pathology images, and curated clinical information. This collaboration harnesses the strengths of academia and industry to provide patient samples, generate high-quality data, develop AI-based analytical tools, and compile a resource that will eventually be made widely available for medical research. Conclusions: Here we present the workflow of the MOSAIC study, demonstrate the data processing pipelines and show spatial distributions of transcripts within the tumor microenvironment. Building upon these initial datasets, we discuss how the MOSAIC parties will collaborate to build an unprecedented database for research and discovery of new immuno-oncology therapeutic approaches.
Genomic characterization of MSI-H and TMB in gastrointestinal cancer.
Authors: Zhi Zheng, Zhouyang Wang, Shaochen Cheng, Yujun Zhou, Wenting Liao, Baoling Zhen, Yaru Chen
Journal: Journal of Clinical Oncology (2023)

e15524 Background: Microsatellite instability (MSI) is a molecular marker of a deficient in mismatch repair (MMR) system. It is one of the main hallmarks in colorectal cancer (CRC) and gastric cancer (GC), occurring in 15% and 18% of CRC and GC respectively. Mutations occur in MMR system genes will impair DNA mismatch recognition and cause accumulation of mutations in DNA microsatellite regions. As a result, microsatellite instability-high (MSI-H) patients often possess an abnormally high number of somatic mutations and would lead to high tumour mutation burden (TMB), which is a prevalent biomarker in cancer immunotherapy. Here we analysed the genomic landscape of 974 gastrointestinal cancer patients to provide new insights on the relationship between MSI, TMB and other genetic mutation characteristics. Methods: Panel sequencing targeting 680 cancer-related genes were performed on patients with colonrectal cancer (n = 569), gastric cancer (n = 375), intestinal cancer (n = 25) and oesophagal cancer (n = 5) on either fresh tumour tissue or formalin-fixed paraffin embedded tumor DNA. Genomic alterations including single nucleotide variations, short insertions and deletions, copy number variations, tumour mutation burden and micro-satellite instability were analysed. Results: Among the 974 patients, 86 patients (8.83%) were classified as MSI-H based on evaluation of 117 MMR-related loci, while rest of the patients (n = 888, 91.2%) were classified as microsatelite stable (MSS). In MSI-H cohort, 68.6% of the patients were classified as TMB-H with a TMB level higher than 10 Muts/Mb, while in MSS cohort, only 3.71% of the patients were classified as TMB-H. The TMB value of MSI-H cohort is also significantly higher than the MSS cohort (p &lt; 0.0001, two-tailed T-test). Meanwhile, we discovered that proportion of patients with mutated lysine methyltransferase family gene KMT2D (54.65% vs 7.17%, p &lt; 0.0001), KMT2B (48.84% vs 3.25%, p &lt; 0.0001) and KMT2C (44.19% vs 7.17%, p &lt; 0.0001) showed significant difference between MSI-H and MSS cohorts (Two-sided Fisher’s exact test). Conclusions: This study demonstrated that MSI-H is highly correlated with TMB-H, providing a new insight of evaluating gastrointestinal cancer treatment on MSI-H patients. The study also revealed novel MSI-H genetic mutation landscape for KMT gene family. Concurrent with recent researches, this study further boosts the potential of KMT genes to be used as a biomarker in both diagnosis and immunotherapy treatment.
<sup>64</sup>Cu-SAR-bisPSMA (PROPELLER) positron emission tomography (PET) imaging in patients with confirmed prostate cancer.
Authors: Eva Lengyelova, Veronica Wong, Nat Lenzo, Michelle Parker, Louise Emmett
Journal: Journal of Clinical Oncology (2023)

5039 Background: Prostate cancer (PC) is the second most frequent malignancy in men globally. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is overexpressed in PC. Recently, several new 68 Ga- and 18 F-based PSMA-targeted PET agents have been approved by the FDA to detect PC, which offer improved sensitivity and specificity compared to traditional imaging. Methods: PROPELLER (NCT04839367) investigated 64 Cu-SAR-bisPSMA in 30 men with untreated, histopathologically proven, primary PC with intermediate- to high-risk features. At screening, patients completed 68 Ga-PSMA-11 PET/CT at 1h post dose. Following enrollment, patients received either 100MBq, 150MBq or 200MBq of 64 Cu-SAR-bisPSMA, followed by PET/CT at 2-4h post dose. Safety was evaluated before and after 64 Cu-SAR-bisPSMA dosing. The 68 Ga-PSMA-11 and 64 Cu-SAR-bisPSMA PET/CT scans were evaluated by 2 independent, blinded central readers for image quality, PC detection, and intensity of tracer uptake in lesions (SUVmax and Tumor-to-Background Ratio [TBR]). Results: A single, Grade 1 64 Cu-SAR-bisPSMA-related AE was reported in the 200MBq cohort. Both readers scored 200MBq of 64 Cu-SAR-bisPSMA as the dose providing the highest image quality. In this cohort, 64 Cu-SAR-bisPSMA and 68 Ga-PSMA-11 was able to detect primary PC in 100% and 77.8% of patients for Reader 1 and 85.7% and 83.3% of patients for Reader 2, respectively. In the 200MBq cohort, Reader 1 identified 41 lesions with 64 Cu-SAR-bisPSMA vs 36 lesions with 68 Ga-PSMA-11, while Reader 2 identified 31 lesions with 64 Cu-SAR-bisPSMA vs 22 lesions with 68 Ga-PSMA-11. In the 200MBq cohort, 64 Cu-SAR-bisPSMA consistently showed higher uptake compared to 68 Ga-PSMA-11 (SUVmax: Reader 1 median [IQR]: 31.40 [27.45] vs 10.08 [13.92], p &lt; 0.001, Reader 2 median [IQR]: 41.00 [46.09] vs 14.58 [14.98], p &lt; 0.001); TBR: Reader 1 median [IQR]: 49.07 [67.69] vs 21.91 [35.71], P = 0.0015), Reader 2 median [IQR]: 76.34 [66.37] vs 23.90 [33.05], p &lt; 0.001). Conclusions: 64 Cu-SAR-bisPSMA was safe and effective for detecting PSMA-expressing lesions. 200 MBq of 64 Cu-SAR-bisPSMA was determined as the optimal dose for future trials. 64 Cu-SAR-bisPSMA PET/CT showed a greater number of lesions and lesions exhibited significantly higher uptake when compared to 68 Ga-PSMA-11 in men being with intermediate- to high-risk PC. Further studies to evaluate 64 Cu-SAR-bisPSMA as an imaging agent in patients with biochemical recurrence of PC are underway. Clinical trial information: NCT04839367 .
Phase II study of biweekly TAS-102, irinotecan and bevacizumab in pre-treated metastatic colorectal cancer (TABAsCO).
Authors: Patrick M Boland, Sarbajit Mukherjee, Iman Imanirad, Namrata Vijayvergia, Seth D. Cohen, Medhavi Gupta, Renuka V. Iyer, Sarah Chatley, Beth Cahill, Deepak Vadehra, Kristopher Attwood, Howard S. Hochster, Christos Fountzilas
Journal: Journal of Clinical Oncology (2023)

3590 Background: The efficacy of 2 nd line FOLFIRI plus VEGF inhibition (VEGFi) is limited for metastatic colorectal cancer (mCRC). TAS-102 is a novel oral anti-metabolite approved for pts with mCRC following standard treatment with FP, oxaliplatin and irinotecan. TAS-102 has a distinct mechanism of action from 5-FU and overcomes 5-FU resistance in preclinical models, and in the clinic. We hypothesized that the combination of TAS-102 with irinotecan (TAS-IRI) and bevacizumab (BEV) would prove superior to FOLFIRI/VEGFi. Methods: Phase II, single-arm study of TAS-IRI and BEV in 2 nd -line mCRC. Eligible patients had received prior treatment with a fluoropyrimidine and oxaliplatin in the advanced setting or experienced recurrence within 12 mos of this regimen in the adjuvant setting. Adequate organ function, ECOG PS 0-1, measurable disease (RECIST 1.1), no prior irinotecan or TAS-102 exposure and candidacy for BEV were required. Pts were treated with BEV 5 mg/kg IV, irinotecan 180 mg/m 2 IV (day 1 and 15), and TAS-102 25 mg/m 2 orally bid (days 2-6 and 16-20) in 4-week cycles (PMID: 31924737). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS). Assuming a median PFS for historic control (FOLFIRI/VEGFi) of 6 mos vs. 9 mos for TAS-IRI plus BEV (HR: 0.67), treatment of 36 evaluable pts would achieve 80.5% power (at α = 0.1) to detect such an effect. Results: Forty-nine patients were enrolled; 42 were eligible and 38 had at least one disease assessment (median age 59 yr, 47% male, 74% colon primary, tumor KRAS/NRAS mutated in 55%/21%). The median PFS was 8.7 mos (range: 6.7-11.8 mos, p = 0.009), meeting the primary endpoint. The most common reason for study treatment discontinuation was progressive disease (53%). The objective response rate was 16% (90% CI: 8.0-27.3%); the median OS was 16.5 mo (range: 11.8-25.3). Twenty-eight pts (67%) had a treatment-related adverse event (TRAE) G3 or higher (Table). The most common TRAEs were gastrointestinal and hematologic. Grade 3/4 neutropenia occurred in 34%, with only 1 episode of febile neutropenia, though G-CSF use was frequently needed to maintain dose density/intensity. Conclusions: TAS-IRI plus BEV is an effective 2 nd line therapy for patients with mCRC. The median PFS appears higher compared to historical controls (FOLFIRI/VEGFi). Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted. (Clinical trial registration ClinicalTrials.gov NCT04109924). Clinical trial information: NCT04109924 . [Table: see text]
Real-world characteristics and treatment pattern of patients with newly diagnosed endometrial cancer in China.
Authors: Aijun Yin, Dong Wang, Yanlin Luo, Ruifang An, Shuzhong Yao, Yufei Shen, Li Sun, Cuirong Lei, Yan Tian, Li Wang, Dan Zhong, Manman Xu, Yuanyuan Jiang, Min Zhang, Binqi Zhang, Huirong Mao, Fengshi Dong, Yu Zhang, Beihua Kong
Journal: Journal of Clinical Oncology (2023)

e17613 Background: Endometrial cancer (EC) is the second most common gynecologic cancer in China with an increasing incidence. Currently, there is no comprehensive profile of EC patients in China. This real-world multicenter retrospective study aimed to depict the characteristics and treatment patterns in newly diagnosed EC patients in China. Methods: Medical records of newly diagnosed EC at 8 hospitals between January 1, 2015 and December 31, 2019 were retrospectively reviewed. The demographic and clinical characteristics at diagnosis as well as the treatment received within 6 months after diagnosis were collected. Results: A total of 1397 patients were enrolled in the study. The average age was 53.5 years. The number of patients (n=1256) classified as stage I, II, III, and IV was 885 (70.5%), 141 (11.2%), 207 (16.5%) and 23 (1.8%), respectively. The number of patients (n=1340) presented with low-grade (G1-2) and high-grade (G3) tumors was 924 (74.0%) and 324 (26.0%), respectively. Invasion of lymphovascular space was detected in 237 (17.0%) out of 1397 patients. Among 1389 patients with pathological data, pure endometrioid carcinoma (90.3%) and serous carcinoma (5.1%) accounted for the majority of pathological types. Estrogen receptor (ER) expression was positive in 91.0% (977/1074) of patients and progesterone-receptor (PR) expression was positive in 85.2% (904/1061) of patients. Mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) was identified in 26.6% (107/402) of patients. Among 1393 patients with treatment information, surgery was performed in 99.6% of patients and 66.9% received adjuvant treatment following surgery according to clinicopathological risk factors. The percentage of patients receiving adjuvant chemotherapy, adjuvant radiotherapy, and adjuvant chemoradiotherapy was 36.7%, 7.3%, and 22.0%, respectively. Among 306 patients who received chemoradiotherapy, 47.1% underwent concurrent chemoradiotherapy, 31.0% underwent sandwich chemoradiotherapy, and 21.9% underwent sequential chemoradiotherapy. Conclusions: To date, this is the first real-world study with largest sample size of EC patients in China. EC is frequently diagnosed at early 50s in Chinese patients, which is at a younger age compared with European and American population. Newly diagnosed EC patients in China are primarily treated with surgery. Chemotherapy and radiotherapy remain the main adjuvant treatment after surgery. MSI-H/dMMR patients accounted for about 1/4 of newly diagnosed patients, for whom immunotherapy may open up better prognosis in the future.
Deep learning tumor heterogeneity metric from histopathology images vs next generation sequencing-derived scores for colon cancer prognostication.
Authors: Hatim Amiji, Todd Brinsley Sheridan, Jeffrey Chuang, Jill Carol Rubinstein
Journal: Journal of Clinical Oncology (2023)

3537 Background: Tumor heterogeneity is as an important determinant of clinical behavior in many cancer types, with increased heterogeneity thought to confer inferior clinical outcome. Sequencing based assessment of colon cancer has been used to quantify tumor heterogeneity and correlate it with survival, but is sensitive to the mutation calling algorithm utilized. Digitization of histopathology slides allows application of deep learning methods for image analysis. Automated slide annotation and feature extraction provides numeric representations of underlying phenotype from which tumor heterogeneity can be estimated. Here we compare the ability of a deep-learning tumor heterogeneity score (THS) to estimate overall survival in colon cancer patients to estimates produced by bulk sequencing derived mutant-allele tumor heterogeneity (MATH) and copy number variation (CNV) event scores. Methods: Digitized whole slide images (WSIs) from The Cancer Genome Atlas (TCGA) colon adenocarcinoma dataset are processed in a computational pipeline for tissue detection, numerical feature extraction, and cell type classification. WSIs are tiled and local THS calculated from imaging features. Corresponding MATH and CNV derived heterogeneity metrics are calculated from published sequencing data. Kaplan Meier curves are used to compare patient survival stratified by tumor heterogeneity as calculated by the three independent methods. Automated regional annotation identifies intra-tumoral and tumor-stromal boundary tiles and tumor THS is correlated to distance from the boundary. Results: Images from 379 patients (209 right-sided, 152 left-sided tumors) yielded 575,762 tiles. Automated annotation resulted in 272,791 intra-tumoral and 11,340 tumor-stromal boundary tiles. Stratification by imaging derived THS provided significant separation of overall survival curves (p &lt; .01) in contrast to MATH and CNV methods (p &gt; .05 for both). THS significantly separated the curves in right- but not left-sided cancers (p = .03 and .44, respectively). Evaluating THS as a function of distance from the tumor-stromal boundary, right-sided tumors showed significant decrease in THS with increasing distance from tumor edge. Conclusions: Our novel pipeline produced spatially resolved imaging data informed by underlying tumor phenotype without need for pathologist annotation. The resultant THS correlated with outcome and outperformed sequencing-based prognostication methods. The spatial information identified higher heterogeneity at the tumor edge than interior regions of right-sided, but not left-sided tumors, capturing known but poorly understood differences in colon tumors by location. Deep learning image analysis provided reproducible and cost-effective data with great potential both in clinical biomarker discovery and as a research tool.
Efficacy of subsequent immunotherapy-tyrosine kinase inhibitor combinations after TKI monotherapy failure in patients with intermediate/poor risk metastatic clear cell renal cell carcinoma: A real-world retrospective study.
Authors: Jie Wu, Wang Qu, Linjun Hu, Aiping Zhou, Jianzhong Shou
Journal: Journal of Clinical Oncology (2023)

e16537 Background: The randomized phase 3 trials KEYNOTE-426, CheckMate 9ER, and CLEAR have demonstrated the efficiency of immunotherapy-based drug combinations as first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). Immunotherapy-tyrosine kinase inhibitor (IO-TKI) has shown significant benefits over sunitinib monotherapy with respect to overall survival in mccRCC patients with intermediate/poor international metastatic database consortium (IMDC risk group). However, most of the patients received second-line TKI or immune checkpoint inhibitors therapy after TKI monotherapy failure in those clinical trials. The role of IO-TKI after disease progression in sunitinib monotherapy cohort was not fully investigated. We sought to evaluate the efficacy of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk who had previously received at least one line of TKI monotherapy. Methods: We conducted retrospective analysis of IMDC intermediate/poor risk mccRCC patients treated with IO-TKI during any treatment line at our center from June 2019 to April 2022. Demographic, clinicopathological, and systemic therapy data were collected. The primary end point was overall survival (OS), defined as the time from initiation of treatment to death from any cause or last follow-up. The secondary end point was progression-free survival (PFS), defined as the time to the first documented disease progression. Results: Overall, 81 IMDC intermediate/poor risk mccRCC patients were enrolled, with a median follow-up of 17 months. 49 patients received first-line IO-TKI therapy, 32 patients who had previously received at least one line of TKI monotherapy received second-line IO-TKI after disease progression. The objective response rate (ORR) and median PFS of second-line IO-TKI after TKI monotherapy failure was 28.6% and 9 months, respectively. OS between first-line IO-TKI therapy and second-line IO-TKI after TKI monotherapy failure was not statistic significant (30 months vs. 26 months, p = 0.630). Conclusions: In this real-world retrospective study, we observed antitumor activity of second-line IO-TKI for mccRCC patients with IMDC intermediate/poor risk after disease progression. Notably, first-line IO-TKI therapy did not have superior OS when TKI monotherapy patients received second-line IO-TKI therapy. Randomized trials are needed to evaluate optimal combination strategies and sequencing of therapies in mccRCC.